The number of deaths from cerebrovascular diseases in Japan had increased until 1970 when it began to decline mostly due to the improvement in their acute-phase therapy. Nevertheless, cerebrovascular diseases remain the second leading cause of death among adult diseases, next only to cancers. As for the incidence of cerebrovascular diseases, many statistical surveys indicate that it is generally constant and in view of the fact that the number of elderly persons will increase at an uncomparably faster speed in Japan than any other country in the world, the number of patients suffering from cerebrovascular diseases is estimated to increase rather than decrease in the future. The declining mortality and the growing population of aged people combine to increase the cases of cerebrovascular diseases in the chronic phase and this has presented with a national problem not only from the aspects of individual patients and society at large but also from the viewpoint of medical economics since patients with chronic cerebrovascular disease are inevitably involved in long-term care. In cerebral infarction that accounts for most cases of cerebrovascular diseases, cerebral arteries are occluded and blood deficit starting at the blocked site extends to the peripheral site, causing an ischemic state. The symptoms of cerebral infarction in the chronic phase are in almost all cases derived from the loss of neurons and it would be extremely difficult to develop medications or established therapeutic methods for achieving complete recovery from those symptoms. Therefore, it is no exaggeration that the improvement in the performance of treatments for cerebral infarction depends on how patients in an acute phase can be treated with a specific view to protecting neurons and how far their symptoms can be ameliorated in the acute phase. However, most of the medications currently in clinical use are antiplatelet drugs, anticoagulants and thrombolytics and none of these have a direct nerve protecting action (see Kazuo MINEMATSU et al., "MEDICINA", published by Igaku Shoin, 32, 1995 and Hidehiro MIZUSAWA et al., published by Nankodo, "Naika" 79, 1997). Therefore, it is desired to develop a drug that provides an effective therapy for cerebrovascular diseases, in particular cerebral infarction, by working in an entirely novel and different mechanism of action from the conventional medications.
A presently dominant theory based on genetic DNA analyses holds that NOS exists in at least three isoforms, namely, calcium-dependent nNOS (type 1) which is present constitutively in neurons, calcium-dependent eNOS (type 3) which is present constitutively in vascular endothelial cells, and apparently calcium-independent iNOS (type 2) which is induced and synthesized by stimulation with cytokines and/or lipopolysaccharides (LPS) in macrophages and many other cells (Nathan et al., FASEB J. 16, 3051-3064, 1992; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995).
A mechanism that has been proposed as being most probable for explaining the brain tissue damage which accompanies cerebral ischemia is a pathway comprising the sequence of elevation in the extracellular glutamic acid level, hyperactivation of glutamic acid receptors on the post-synapses, elevation in the intracellular calcium level and activation of calcium-dependent enzymes (Siesjo, J. Cereb. Blood Flow Metab. 1, 155-185, 1981; Siesjo, J. Neurosurg. 60, 883-908, 1984; Choi, Trends Neurosci. 11, 465-469, 1988; Siesjo and Bengstsson, J. Cereb. Blood Flow Metab. 9, 127-140, 1989). As already mentioned, nNOS is calcium-dependent, so the inhibition of hyperactivation of this type of NOS isoforms would contribute to the neuro-protective effects of NOS inhibitors (Dawson et al., Annals Neurol. 32, 297-311, 1992).
As a matter of fact, the mRNA level of nNOS and the number of nNOS containing neurons start to increase early after focal cerebral ischemia in rats and their temporal alterations coincide with the development of infarction (Zhang et al., Brain Res. 654, 85-95, 1994). In addition, in a mouse model of focal cerebral ischemia, the percent inhibition of nNOS activity and the percent reduction of infarct volume correlate to each other at least in a dose range of N.sup.G -nitro-L-arginine (L-NA) that produces a recognizable infarct volume reductive action (Carreau et al., Eur. J. Pharmacol. 256, 241-249, 1994). Further in addition, it has been reported that in nNOS knockout mice, the infarct volume observed after focal cerebral ischemia is significantly smaller than that in the control (Huang et al., Science 265, 1883-1885, 1994).
Referring now to NO, it is at least one of the essences of endothelium-derived relaxing factor (EDRF) and, hence, is believed to take part in the adjustment of the tension of blood vessels and the blood flow (Moncade et al., Pharmacol. Rev. 43, 109-142, 1991). As a matter of fact, it was reported that when rats were administered high doses of L-NA, the cerebral blood flow was found to decrease in a dose-dependent manner as the blood pressure increased (Toru MATSUI et al., Jikken Igaku, 11, 55-60, 1993). The brain has a mechanism by which the cerebral blood flow is maintained at a constant level notwithstanding the variations of blood pressure over a specified range (which is commonly referred to as "autoregulation mechanism") ("NOSOTCHU JIKKEN HANDBOOK", complied by Keiji SANO, published by IPC, 247-249, 1990). The report of Matsui et al. suggests the failure of this "autoregulation mechanism" to operate. Therefore, if eNOS is particularly inhibited beyond a certain limit in an episode of brain ischemia, the cerebral blood flow will decrease and the blood pressure will increase, thereby aggravating the dynamics of microcirculation, possibly leading to an expansion of the ischemic lesion. It was also reported that in eNOS knockout mice, the infarct observed after focal cerebral ischemia was larger than that in the control but could be reduced significantly by administration of L-NA (Huang et al., J. Cereb. Blood Flow Metab. 16, 981-987, 1996). These reports show that eNOS-derived NO probably works protectively on the brain tissue through the intermediary of a vasodilating action, a platelet aggregation suppressing action and so forth.
The present inventors previously found that L-NA, already known to be a NOS inhibitor, possessed ameliorative effects on the brain edema and cerebral infarction following phenomena that developed after experimental cerebral ischemia (Nagafuji et al., Neurosci. Lett. 147, 159-162, 1992; Japanese Patent Public Disclosure No. 192080/1994), as well as necrotic neuronal cell death (Nagafuji et al., Eur. J. Pharmacol. Env. Tox. 248, 325-328, 1993). On the other hand, relatively high doses of NOS inhibitors have been reported to be entirely ineffective against ischemic brain damage and sometimes aggravating it (Idadecola et al., J. Cereb. Blood Flow Metab. 14, 175-192, 1994; Toshiaki NAGAFUJI and Toru MATSUI, Jikken Igaku, 13, 127-135, 1995; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995). It should, however, be stressed that as a matter of fact, all papers that reported the changes of NO or NO-related metabolites in the brain and blood in permanent or temporary cerebral ischemic models agreed in their results to show the increase in the levels of those substances (Toshiaki NAGAFUJI and Toru MATSUI, Jikken Igaku, 13, 127-135, 1995; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995).
One of the reasons for explaining the fact that conflicting reports have been made about the effectiveness of NOS inhibitors in cerebral ischemic models would be the low selectivity of the employed NOS inhibitors for nNOS. As a matter of fact, no existing NOS inhibitors including L-NA and N.sup.G -nitro-L-arginine methyl ester (L-NAME) have a highly selective inhibitory effect on a specific NOS isoform (Nagafuji et al. Neuroreport 6, 1541-1545, 1995; Nagafuji et al. Mol. Chem. Neuropathol. 26, 107-157, 1995). Therefore, it may well be concluded that desirable therapeutics of ischemic cerebrovascular diseases should have a selective inhibitory effect on nNOS (Nowicki et al., Eur. J. Pharmacol. 204, 339-340, 1991; Dawson et al., Proc. Natl. Acad. Sci. USA 88, 6368-6371, 1991; Iadecola et al., J. Cereb. Blood Flow Metab. 15, 52-59, 1995; Iadecola et al., J. Cereb. Blood Flow Metab. 15, 378-384, 1995; Toshiaki NAGAFUJI and Toru MATSUI, Jikken Igaku 13, 127-135, 1995; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995).
It has also been suggested that nNOS inhibitors have the potential for use as therapeutics of traumatic brain injuries (Oury et al., J. Biol. Chem. 268, 15394-15398, 1993; MacKenzie et al., Neuroreport 6, 1789-1794, 1995; Mesenge et al., J. Neurotrauma. 13, 11-16, 1996; Wallis et al., Brain Res., 710, 169-177, 1996), headache and other pains (Moore et al., Br. J. Pharmacol. 102, 198-202, 1991; Olesen., Trends Pharmacol. 15, 149-153, 1994), Parkinson's disease (Youdim et al., Advances Neurol. 60, 259-266, 1993; Schulz et al., J. Neurochem. 64, 936-939, 1995; Hantraye et al., Nature Medicine 2, 1017-1021, 1996), Alzheimer's disease (Hu and EI-FaKahany, Neuroreport 4, 760-762, 1993 Meda et al., Nature 374, 647-650, 1995), seizure (Rigaud-Monnet et al., J. Cereb. Blood Flow Metab. 14, 581-590, 1994), and morphine tolerance and dependence (Kolesnikov et al., Eur. J. Pharmacol. 221, 399-400, 1992; Cappendijk et al., Neurosci. Lett. 162, 97-100, 1993).
Upon stimulation by certain kinds of cytokines and/or LPS, iNOS is induced in immunocytes such as macrophages and glial cells and other cells, and the resulting large amount of NO will dilate blood vessels to cause a fatal drop in blood pressure. Therefore, it is speculated that an iNOS inhibitor may be effective against septic shocks (Kilbourn and Griffith, J. Natl. Cancer Inst. 84, 827-831, 1992; Cobb et al., Crit. Care Med. 21, 1261-1263, 1993; Lorente et al., Crit. Care Med. 21, 1287-1295, 1993). Further, it has been suggested that iNOS inhibitors are useful as therapeutics of chronic rheumatoid arthritis and osteoarthritis (Farrell et al., Ann, Rheum. Dis. 51, 1219-1222, 1992; Hauselmann et al., FEBS Lett. 352, 361-364, 1994; Islante et al., Br. J. Pharmacol. 110, 701-706, 1993), viral or nonviral infections (Zembvitz and Vane, Proc. Natl. Acad. Sci. USA 89, 2051-2055, 1992; Koprowski et al., Proc. Natl. Acad. Sci. USA 90, 3024-3027, 1993) and diabetes mellitus (Kolb et al., Life Sci. PL213-PL217, 1991).
The NOS inhibitors so far reported to have a certain degree of selectivity for nNOS are N.sup.G -cyclopropyl-L-arginine (L-CPA)(Lamberte et al., Eur. J. Pharmacol. 216, 131-134, 1992), L-NA (Furfine et al., Biochem. 32, 8512-8517, 1993), S-methyl-L-thiocitrulline (L-MIN) (Narayanan and Griffith, J. Med. Chem. 37, 885-887, 1994; Furfine et al., J. Biol. Chem. 37, 885-887, 1994; Furfine et al. J. Biol. Chem. 269, 26677-26683, 1994; WO95/09619; Narayanan et al., J. Biol. Chem. 270, 11103-11110, 1995; Nagafuji et al., Neuroreport 6, 1541-1545, 1995), S-ethyl-L-thiocitrulline (L-EIN) (Furfine et al., J. Biol. Chem. 269, 26677-26683, 1994; WO95/09619; Narayanan et al., J. Biol. Chem. 270, 11103-11110, 1995), and ARL 17477 (Gentile et al., WO95/05363; Zhang et al., J. Cereb. Blood Flow Metab., 16, 599-604, 1996).
In addition, the inhibitors that have been reported to have a certain degree of selectivity for iNOS are N.sup.G -iminoethyl-L-ornithine (L-NIO) (McCall et al., Br. J. Pharmacol. 102, 234-238, 1991) and aminoguanidine (AG) (Griffith et al., Br. J. Pharmacol. 110, 963-968, 1993; Hasan et al. Eur. J. Pharmacol. 249, 101-106, 1993).